A stereospecific palladium-catalyzed route to monoalkyl diazenes for mild allylic reduction

Article abstract of DOI:10.1002/anie.200802921

(Chemical Equation Presented) One step beyond: The first single-step stereospecific transition-metal-catalyzed conversion of allylic electrophiles into monoalkyl diazenes is described. This synthesis of allylic monoalkyl diazenes offers a new strategy for asymmetric synthesis by the reduction of optically active substrates or the use of chiral catalyst systems. Sensitive substrates are reduced in a highly selective manner. Ar = 2-NO₂C ₆H₂.

Full text of DOI:10.1002/anie.200802921

Angewandte
Chemie
DOI: 10.1002/anie.200802921
Synthetic Methods
A Stereospecific Palladium-Catalyzed Route to Monoalkyl Diazenes
for Mild Allylic Reduction**
Mohammad Movassaghi* and Omar K. Ahmad
Transition-metal-catalyzed allylic alkylation reactions have
been utilized extensively in synthetic organic chemistry.[1]
These reactions include many powerful transformations that
focus on carbon–heteroatom bond formation,including
reports concerning the use of nitrogen nucleophiles.[2]
Herein we report the first example of a stereospecific
transition-metal-catalyzed conversion of allylic electrophiles
into the corresponding monoalkyl diazenes for a mild and
highly stereoselective reduction in a single operation. This
palladium-catalyzed diazene synthesis offers opportunities
for asymmetric synthesis by the stereospecific reduction of
optically active substrates or the use of chiral catalyst systems,
using vinyl epoxide and allylic carbonate substrates,respec-
tively.
give the allylic diazene 6 and,upon sigmatropic loss of
dinitrogen,afford the desired product 7. The use of 1a in
place of diimide enables the conversion of 3 into diazene 6
without isolation of intermediates.
We initially focused on the development of efficient
conditions for the Pd-catalyzed allylation of sulfonylhydra-
zones (Table 1). Allylic carbonates,such as 2a,were found to
Table 1: Sulfonylhydrazone nucleophiles.[a]
We recently reported the use of N-isopropylidene-N’-2-
nitrobenzenesulfonylhydrazide (IPNBSH, 1a) for the con-
version of alcohols into the corresponding monoalkyl di-
azenes by the Mitsunobu reaction.[3,4] Our findings regarding
the chemistry of 1a led us to investigate its use as a diimide
surrogate in the transition-metal-catalyzed synthesis of mono-
alkyl diazenes (Scheme 1). We envisioned the reaction of the
p-allyl complex 3 with sulfonylhydrazone 1a to give hydra-
zone 4.[5] In situ hydrolysis and fragmentation of 4[3,6] would
MNuc:
M=K, 1b, 88%
1d, 96%
1e, 97%
M=Li, 1c, 79%[b]
1 f, 81%
1g, 86%
1h, 84%
[a] Yields given are for the isolated corresponding adducts 4’; average of
two experiments. [b] [12]Crown-4 (10 mol%) was added to the reaction
mixture.
be superior substrates to allylic bromides or allylic acetates.[7]
The use of sulfonamide salts enhanced the rate of the desired
palladium-catalyzed allylic alkylation.[7] The optimal condi-
tions for this transformation involved the treatment of allylic
carbonate 2a with [{(h3-allyl)PdCl}2] (2.5 mol%),triphenyl-
phosphine (10 mol%),and potassium sulfonylhydrazide 1b
(1.0 equiv)[7,8] at 238C for 24 h,affording the desired adduct 4’
in 88% yield (Table 1). These reaction conditions are
effective with both aldehyde- and ketone-derived sulfonylhy-
drazone salts as nucleophiles. Methanesulfonyl- and arene-
sulfonylhydrazones derived from both saturated and unsatu-
rated carbonyl precursors were successfully converted into
the desired hydrazone adducts.[9] Whereas the potassium
derivative 1b proved a more effective reagent than the
analogous lithium derivative 1c,where possible,the greater
solubility of the lithium sulfonylhydrazides was advantageous
in leading to faster reactions and higher conversions.
Scheme 1. Metal-catalyzed synthesis of allylic diazenes and subsequent
loss of N2. IPNBSH=N-isopropylidene-N’-2-nitrobenzenesulfonylhy-
drazide; Ar=2-NO2C6H4.
[*] Prof. Dr. M. Movassaghi, O. K. Ahmad
Department of Chemistry, Massachusetts Institute of Technology
Cambridge, Massachusetts 02139 (USA)
E-mail: movassag@mit.edu
Homepage: http://web.mit.edu/movassag/www/index.htm
[**] M.M. is a Beckman Young Investigator and a Sloan Research Fellow.
O.K.A is grateful for a Merck graduate fellowship. We acknowledge
financial support by the NSF (547905), AstraZeneca, Amgen, Eli
Lilly, GlaxoSmithKline, Merck Research Laboratories, and Boeh-
ringer Ingelheim Pharmaceutical Inc.
We next explored the applicability of these conditions to
the palladium-catalyzed displacement of a range of allylic
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802921.
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carbonates (2’) with the reagent 1b (Table 2). Gratifyingly,
favoring conjugated products,as illustrated by the exclusive
isolation of adduct 4a [Eq. (1)] from carbonate 2b if no water
is added to the reaction mixture (Table 2,entry 7).
the desired palladium-catalyzed displacement chemistry fol-
lowed by mild in situ hydrolysis[3] proved effective for a wide
range of both primary and secondary allylic carbonate
Table 2: Reduction of allylic carbonates.
Entry
1
Substrate
Product
Yield [%][a]
76[b]
Entries 6–8 of Table 2 are consistent with net SN2’
displacement of carbonates with reagent 1b to give conju-
gated sulfonylhydrazones that are ultimately subject to
sigmatropic loss of dinitrogen,affording the unconjugated
products. For comparison,treatment of methyl 5-phenylpent-
1-en-3-yl carbonate with 1b under the optimal conditions
gives 5-phenylpent-1-ene (Table 2,entry 5),whereas treat-
ment of the corresponding alcohol,5-phenylpent-1-en-3-ol,
with 1a under Mitsunobu conditions affords the isomeric (E)-
5-phenylpent-2-ene as a result of direct SN2 displacement with
2
86
3
4
91
59[b,c]
[3,7]
1a,followed by loss of dinitrogen.
Vinyl epoxides also serve as substrates[13] for this palla-
dium-catalyzed synthesis of allylic diazenes. The use of
[Pd2(dba)3] in conjunction with 1a and cesium carbonate as
the base additive efficiently provided the desired reduction
product (Scheme 2). This chemistry provides a mild and
5
6
75
82[d]
7
54[d]
8
9
73[e]
68
[a] Yield of the isolated reduction product; average of two experiments.
[b] E:Z, 95:5. [c] Modified conditions: 1a (1 equiv) and Na2CO3
(10 mol%) used in place of 1b in CH2Cl2. [d] E:Z, 96:4. [e] C2 E:Z,
96:4; C5 E:Z, 95:5. TFE=trifluoroethanol, AcOH=acetic acid.
Scheme 2. Palladium-catalyzed conversion of allylic epoxides into
allylic diazenes and subsequent loss of N2. dba=dibenzylideneace-
tone.
substrates. Even highly sensitive substrates,such as the
doubly activated carbonates (Table 2,entries 6–8),were
successfully converted into the corresponding adducts (4,
Scheme 1) and hydrolyzed to give the desired reduction
products. Significantly,the use of analogous doubly activated
alcohol substrates under Mitsunobu reaction conditions or
metal hydride reduction of the corresponding carbonate
derivative resulted in significant decomposition and elimina-
tion.[7,10] For example,treatment of carbonate 2b with
tris(dibenzylideneacetone)dipalladium,tri- n-butylphosphine,
and ammonium formate in 1,4-dioxane led to significant
decomposition of the starting material and afforded < 15% of
the desired unconjugated product (compare to Table 2,
entry 7).[7,10] Furthermore,the regioselective reduction of
substrates (Table 2,entries 4–9) demonstrates the versatility
of this method in comparison to alternative free-radical-based
reductions,[7,11] which lead to complex mixtures of products.
Whereas the high level of stereoselectivity for E-alkene
products is due to the sigmatropic loss of dinitrogen from an
allylic diazene intermediate,[4b,12] the regiochemical prefer-
ence in the reduction reflects the initial adduct formation
highly stereoselective conversion of allylic epoxides into the
corresponding homoallylic alcohol products. As shown in
Scheme 2,reduction of optically active Z-allylic epoxide 8a
(> 98% ee) under the aforementioned reaction conditions
gave the desired syn-homoallylic alcohol 9a (> 98% ee) in
79% yield.[7] The product is isolated as the E alkene (> 98:2,
E:Z),as expected for fragmentation of allylic diazene
intermediates.[4b,12]
Additionally,treatment of the isomeric E-allylic epoxide
8b resulted in the stereoselective synthesis of the anti-
homoallylic alcohol derivative 9b [Eq. (2)].[7] It should be
noted that the use of formic acid as the reducing agent in the
palladium-catalyzed reduction of 8a affords the anti-diaste-
reoisomer 9b,[14] highlighting the distinction between the
reduction described herein and other related processes.
The aforementioned transformations highlight the poten-
tial development of catalytic asymmetric variants of this
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reduction chemistry.[1] The treatment of carbonate (Æ )-2c
and reagent 1b with a catalyst system comprised of Trostꢀs[15]
(1S,2S)-(À)-1,2-diaminocyclohexane-N,N’-bis(2’-diphenyl-
phosphinobenzoyl) ligand ((À)-10,7.5 mol%) and [( h3-
allyl)PdCl]2 (2.5 mol%) gave the sulfonylhydrazone adduct
(+)-4b in 91% yield and 94% ee [Eq. (3)]. Mild hydrolysis of
hydrazone (+)-4b afforded the optically active ester (+)-7a
in 88% yield and 94% ee. The absolute configuration of
adduct (+)-4b was established by comparison of the optical
rotation of the product (+)-7a with literature values.[7]
Notably,the conversion of ( Æ )-2c into (+)-7a can be
effected,without isolation of hydrazone intermediate ( +)-
4b,by direct hydrolysis after complete consumption of ( Æ )-
2c,affording ( +)-7a in 71% yield.[7]
In summary,a mild and highly stereoselective reduction of
allylic carbonates and vinyl epoxide substrates is described.
Palladium-catalyzed activation of allylic electrophiles effi-
ciently provided a range of N-alkylated sulfonylhydrazones.
N-allylated derivatives of IPNBSH (1a) were prepared using
this method and their in situ hydrolysis provided access to the
corresponding reduction products. This chemistry offers a
unique solution to stereospecific synthesis of monoalkyl
diazene intermediates from allylic electrophiles under mild
reaction conditions. Sensitive substrates that are incompatible
with other methods were reduced in a highly stereoselective
and regioselective manner. The catalytic asymmetric activa-
tion of electrophiles coupled with this new route to allylic
monoalkyl diazenes offers additional opportunities for asym-
metric synthesis.
Received: June 18,2008
Revised: September 5,2008
Published online: October 16,2008
Keywords: allylic compounds · asymmetric synthesis ·
.
homogeneous catalysis · hydrazones · reduction
Furthermore,treatment of the meso-dicarbonate 11a with
reagent 1b,under the optimized reaction conditions with
ligand (+)-10,afforded the adduct ( +)-12a in > 85% yield
and 98% ee [Eq. (4)].[16] The ready availability of both
enantiomers of the ligand 10 gives easy access to either
enantiomer of the desired adduct and the corresponding
reduction product [Eq. (5)]. Notably,this chemistry is also
amenable to the use of allylic benzoate electrophiles. The
catalytic asymmetric synthesis of the adduct (+)-12b pro-
ceeded with a good level of enantioselection (93% ee),albeit
with a slower reaction rate as compared to allylic carbonates
or epoxides [Eq. (6)]. The mild hydrolysis of the hydrazone
adducts 12a and 12b provided the corresponding reductively
transposed products (+)-13a and (+)-13b [Eqs. (4) and
(6)].[16,17]
[1] B. M. Trost,M. L. Crawley, Chem. Rev. 2003, 103,2921.
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M. A. Ariger,P. Moriel,E. M. Carreira, Angew. Chem. 2007,
119,3200; Angew. Chem. Int. Ed. 2007, 46,3139; d) A. M. Johns,
Z. Liu,J. F. Hartwig, Angew. Chem. 2007, 119,7397; Angew.
Chem. Int. Ed. 2007, 46,7259; e) I. Dubovyk,I. D. G. Watson,
A. K. Yudin, J. Am. Chem. Soc. 2007, 129,14172; f) also,see
L. E. Overman, J. Am. Chem. Soc. 1976, 98,2901.
[3] M. Movassaghi,O. K. Ahmad, J. Org. Chem. 2007, 72,1838.
[4] a) A. G. Myers,B. Zheng, J. Am. Chem. Soc. 1996, 118,4492;
b) A. G. Myers,B. Zheng, Tetrahedron Lett. 1996, 37,4841.
[5] a) For a review on N nucleophiles,see M. Johannsen,K. A.
Jorgensen, Chem. Rev. 1998, 98,1689; b) For an example of Pd-
catalyzed N-allylation of benzophenone hydrazones,see
Ref. [2d]; c) for an example of Ir-catalyzed N-allylation of a
tosylhydrazone,see R. Matunas,A. J. Lai,C. Lee, Tetrahedron
2005, 61,6298; d) for an example of carbonium ion trapping by a
sulfonylhydrazide leading to an allylic reduction,see J. L. Wood,
J. A. Porco,Jr.,J. Taunton,A. Y. Lee,J. Clardy,S. L. Schreiber, J.
Am. Chem. Soc. 1992, 114,5898.
[6] a) S. Hꢁnig,H. R. Mꢁller,W. Thier, Angew. Chem. 1965, 77,368;
Angew. Chem. Int. Ed. Engl. 1965, 4,271; b) E. M. Kosower, Acc.
Chem. Res. 1971, 4,193; c) E. J. Corey,D. E. Cane,L. Libit, J.
Am. Chem. Soc. 1971, 93,7016.
[7] See the Supporting Information for details.
[8] Treatment of 1a with KH affords the stable and storable 1b.
[9] As well as being versatile synthetic intermediates,hydrazones
are also utilized as dyes and as pharmacologically active
compounds.
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Communications
[10] For a review,see: J. Tsuji,T. Mandai, Synthesis 1996,1.
[11] S. Maity,S. Ghosh, Tetrahedron Lett. 2007, 48,3355.
[12] A. G. Myers,P. J. Kukkola, J. Am. Chem. Soc. 1990, 112,8208.
[13] B. M. Trost,R. C. Bunt,R. C. Lemoine,T. L. Calkins,
Chem. Soc. 2000, 122,5968.
[16] The absolute configurations given in [Eq. (4)–(6)] are based on
analogy to other nucleophiles used in these systems. See:
a) B. M. Trost,G. G. Cook, Tetrahedron Lett. 1996, 37,7485;
b) B. M. Trost,L. S. Chupak,T. Lꢁbbers, J. Am. Chem. Soc. 1998,
120,1732.
J. Am.
[17] Substrates (Æ )-2c and 11a provide examples of both sym-
metrical and asymmetrical electrophilic p-allyl ligands,respec-
tively,successfully incorporated in the intermediate Pd complex
in these processes.
[14] M. Oshima,H. Yamazaki,I. Shimizu,M. Nisar,J. Tsuji,
Chem. Soc. 1989, 111,6280.
[15] B. M. Trost,R. C. Bunt, J. Am. Chem. Soc. 1994, 116,4089.
J. Am.
8912
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